Project Summary Coronary heart disease is the leading cause of death in the U.S., and patients who survive a coronary artery occlusion have a high risk for cardiac arrhythmias and sudden cardiac death. Spatial heterogeneity of sympathetic transmission is a major contributor to post-infarct arrhythmias and sudden cardiac death after myocardial infarction (MI), and sympathetic denervation predicts arrhythmia risk in human studies. During the previous period of support we discovered that persistent denervation was caused by chondroitin sulfate proteoglycans (CSPGs) in the scar acting on neuronal Protein Tyrosine Phosphatase Receptor Sigma (PTP?). Targeting PTP? using genetics or the therapeutic peptide ISP promoted reinnervation. Deletion of PTP? normalized myocyte ?-AR signaling, cardiac electrophysiology, and myocyte Ca2+ handling, rendering hearts resistant to isoproterenol-induced arrhythmias. We hypothesize that it is reinnervation, not the lack of PTP?, which normalizes cardiac electrophysiology and Ca2+ handling after MI. We will test that hypothesis using two therapeutics to restore cardiac nerves: ISP which targets PTP?, and a novel small molecule (HJ-2) which binds TrkA. This will allow us to distinguish the effects of reinnervation, which is stimulated by both drugs, from other drug-specific effects. We will determine if reinnervation normalizes cardiac electrophysiology and Ca2+ handling, if reinnervation and its effects are sustained, and if noradrenergic transmission is required for restoring electrical stability in the heart. We will determine if sympathetic reinnervation during scar maturation enhances cardiac repair or alters the inflammatory response, and if delayed reinnervation is protective. We have assembled an outstanding team of experts along with novel chemical reagents and imaging tools to assist us in completing these studies. This work will test if stimulating nerve regeneration with therapeutics can normalize cardiac electrophysiology and decrease arrhythmias, and will identify the mechanisms involved.